RATIONALE: Drugs used in chemotherapy, such as doxorubicin and flavopiridol, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Flavopiridol may also help doxorubicin work better by making tumor cells more sensitive to the drug. Giving more than one drug may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of flavopiridol when given with doxorubicin in treating patients with metastatic or recurrent sarcoma that cannot be removed by surgery.

Condition	Treatment or Intervention	Phase
gastrointestinal stromal tumor recurrent adult soft tissue sarcoma stage IV adult soft tissue sarcoma	Drug: doxorubicin  Drug: flavopiridol  Procedure: chemosensitization/potentiation  Procedure: chemotherapy	Phase I

Further Study Details: 

OBJECTIVES: Primary

• Determine the maximum tolerated dose of flavopiridol when administered with a fixed dose of doxorubicin in patients with unresectable metastatic or locally recurrent sarcoma.

Secondary

• Determine the clinical pharmacokinetics of this regimen in these patients.
• Determine, preliminarily, the therapeutic activity of this regimen in these patients.
• Correlate pRb, p53, and p21 protein levels with treatment response and apoptosis in patients treated with this regimen.
• Correlate NMR biochemical patterns with response in patients treated with this regimen.

OUTLINE: This is an open-label, dose-escalation study of flavopiridol.

Patients receive doxorubicin IV over 5-10 minutes and flavopiridol IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients reaching a cumulative doxorubicin dose of 600 mg/m^2 or experiencing cardiotoxicity may receive flavopiridol alone at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Ten additional patients receive treatment at the MTD.

Patients are followed every 3 months for 1 year.

PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 1-2 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed soft-tissue sarcoma*
• Unresectable disease
• Locally recurrent or metastatic disease
• Disease amenable to biopsy (patients treated at the maximum tolerated dose only)
• No known prior or concurrent brain metastases NOTE: *Patients with gastrointestinal stromal tumors should receive therapy with imatinib mesylate first if eligible for both types of therapy

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• Karnofsky 60-100% OR
• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• Ejection fraction ≥ 50% by MUGA or echocardiogram
• No uncontrolled hypertension
• No myocardial infarction
• No New York Heart Association class II-IV congestive heart failure
• No unstable angina
• No serious cardiac arrhythmia requiring medication
• No peripheral vascular disease ≥ grade 2 within the past year
• No other clinically significant cardiac disease
• No prior deep vein thrombosis
• No other prior vascular thrombus

Pulmonary

• No prior pulmonary embolism

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No symptomatic peripheral neuropathy ≥ grade 2
• No other malignancy within the past 5 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix
• Carcinoma in situ not considered a second malignancy
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs
• No psychiatric illness or social situation that would preclude study compliance
• No ongoing or active infection
• No other uncontrolled illness

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Chemotherapy
• At least 3 weeks since prior immunotherapy and recovered

Chemotherapy

• At least 3 weeks since prior chemotherapy (6 weeks for carmustine or mitomycin) and recovered
• No more than 2 prior chemotherapy regimens
• Peroxisome proliferator-activated receptor (PPAR)-gamma agonists, imatinib mesylate, or thalidomide do not count as a prior chemotherapy regimen
• No prior anthracyclines

Endocrine therapy

• Not specified

Radiotherapy

• At least 3 weeks since prior radiotherapy and recovered
• No prior extensive radiotherapy to bone marrow-producing sites (e.g., radiotherapy to both the pelvis and spine)

Surgery

• Not specified

Other

• Concurrent low-dose warfarin (1 mg per day) to prevent thrombus of a central line allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer therapy

New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States; Recruiting

Study chairs or principal investigators

David R. D'Adamo, MD, PhD,  Principal Investigator,  Memorial Sloan-Kettering Cancer Center   

Study ID Numbers:  CDR0000398181; MSKCC-04075; NCI-6204; NCT00098579
Record last reviewed:  November 2004
Last Updated:  February 4, 2005
Record first received:  December 7, 2004
ClinicalTrials.gov Identifier:  NCT00098579
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08